The microbiota influences many aspects of human health, but the mechanisms that balance it remain incompletely understood. Our previous work has established the concept that enteric pathogens act as ecosystem engineers by using their virulence factors to manipulate host habitat filters, thereby constructing new nutrient-niches that support their invasion of the gut ecosystem. Thus, mucosal pathogens are valuable tools for identifying host-derived habitat filters that structure the microbiota. Our long-range goal is to identify host-derived habitat filters that shape the microbiota by using Citrobacter rodentium as a tool to identify environmental factors that allow the pathogen to edge out gut-associated microbial communities. The objectives of this application are to study how its main virulence factor, the type III secretion system (T3SS), helps C. rodentium to prevent pathogen extinction during the initial phase of infection. Our central hypothesis is that virulence factors provide C. rodentium with access to epithelial hydrogen peroxide, a host habitat filter that sustains pathogen growth early after infection. We will test different aspects of our hypothesis by determining whether intimate attachment mediated by the T3SS provides C. rodentium access to NOX1-derived hydrogen peroxide (H2O2) and determining the role NOX1-derived H2O2 plays as a habitat filter structuring the spatial organization of the gut microbiota. The proposed work makes innovative use of mucosal pathogens to provide fundamental insights into microbiome research and we expect that a successful completion will offer mechanistic insights into host habitat filters selecting for microbial traits that permit survival and growth in the host. By establishing the identity of a novel host-derived habitat filter, our research will be of wide appeal among researchers interested in microbial pathogenesis and the nutritional environment that shapes our host-associated microbial communities.
An imbalance in host-associated microbial communities (dysbiosis) may underlie many human diseases, but the mechanisms involved in disrupting homeostasis remain poorly understood. Here we will study the mechanisms through which a luminal enteric pathogen, Citrobacter rodentium, uses its virulence factors to disrupt a balanced microbiota composition in the gut to drive a dysbiotic pathogen expansion. The resulting knowledge will usher in important conceptual advances on how the host controls the nutritional environment of microbes colonizing mucosal surfaces, which will have a strong potential to exert a high impact on the fields of microbial pathogenesis and microbiota research.
